rs6434313

Positions:

• chr2-189051384-C-G
• chr2-189051384-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000393.5(COL5A2):​c.2867G>C​(p.Arg956Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000537 in 1,614,048 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (4 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.07

Genes affected

COL5A2 (HGNC:2210): (collagen type V alpha 2 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL5A2. . Gene score misZ 2.4395 (greater than the threshold 3.09). Trascript score misZ 3.3523 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, classic type, 2, Ehlers-Danlos syndrome, classic type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.013373345).
• BP6: Variant 2-189051384-C-G is Benign according to our data. Variant chr2-189051384-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 136948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00278 (423/152242) while in subpopulation AFR AF= 0.00975 (405/41542). AF 95% confidence interval is 0.00897. There are 3 homozygotes in gnomad4. There are 196 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 423 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.2867G>C	p.Arg956Pro	missense_variant	42/54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.2729G>C	p.Arg910Pro	missense_variant	45/57		XP_011508875.1
COL5A2	XM_047443251.1	c.2729G>C	p.Arg910Pro	missense_variant	47/59		XP_047299207.1
COL5A2	XM_047443252.1	c.2729G>C	p.Arg910Pro	missense_variant	46/58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.2867G>C	p.Arg956Pro	missense_variant	42/54	1	NM_000393.5	ENSP00000364000	P1
COL5A2	ENST00000618828.1	c.1706G>C	p.Arg569Pro	missense_variant	35/47	5		ENSP00000482184

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 421 AN: 152122 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00973

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.000661 AC: 166 AN: 251280 Hom.: 1 AF XY: 0.000434 AC XY: 59 AN XY: 135812

Gnomad AFR exome AF: 0.00961

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000304 AC: 444 AN: 1461806 Hom.: 4 Cov.: 31 AF XY: 0.000276 AC XY: 201 AN XY: 727196

Gnomad4 AFR exome AF: 0.0109

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.00278 AC: 423 AN: 152242 Hom.: 3 Cov.: 32 AF XY: 0.00263 AC XY: 196 AN XY: 74436

Gnomad4 AFR AF: 0.00975

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.00302

ESP6500AA AF: 0.0102 AC: 45

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000832 AC: 101

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	COL5A2: BS1, BS2 -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome, classic type, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 16, 2020

- -

Ehlers-Danlos syndrome, classic type, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Benign	0.82
DEOGEN2	Benign	0.14	T;T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.86	.;D;D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	-0.88	N;.;N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.47	N;.;.
REVEL	Benign	0.19
Sift	Benign	0.55	T;.;.
Sift4G	Benign	0.85	T;T;.
Polyphen		0.15	B;.;B
Vest4		0.67
MVP		0.44
MPC		0.37
ClinPred		0.031	T
GERP RS		5.0
Varity_R		0.16
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6434313; hg19: chr2-189916110;